DESCRIPTION (Applicant's abstract): Circulating glucose concentration is monitored and maintained at appropriate concentrations by the central nervous system (CNS). Physiological and behavioral responses to glucose imbalances have been described, but the key mechanism by which fluctuations in glucose status are recognized and appropriate counter-regulatory responses initiated is not known. The immediate objective of the proposed research is to identify underlying neurochemical mechanisms in the ventral hypothalamus that sense changes in plasma glucose and initiate counterregulatory responses to restore glucose status. Noradrenergic activity in the ventromedial hypothalamus (VMH) has been demonstrated to influence blood glucose through effects on the autonomic nervous system, behavior, and neuroendocrine system. We have reported a consistent activation of noradrenergic systems in the VMH during hypoglycemia. The specific aims of this application are to determine the glycemic thresholds for the activation of noradrenergic systems in the VMH, to evaluate the effect of changes in interstitial fluid glucose concentrations in the VMH on noradrenergic activation, to determine if the activation of noradrenergic systems in the VMH is mediated through local intrinsic neurons within the VMH, to the effect of recurrent hypoglycemia on the noradrenergic activation in the VMH, and determine if increased levels of circulating leptin alter sensitivity of noradrenergic response to hypoglycemia. Intravenous catheters and microdialysis probes will be used to simultaneously monitor plasma glucose and concentrations of extracellular neurotransmitters in the VMH. Our hypothesis is that glucose responsive neurons in the VMH respond to changes in extracellular glucose concentrations that reflect circulating plasma glucose and activates noradrenergic inputs to the hypothalamus. The activation of these neurons is dynamic, so that the glycemic threshold for activating NE systems in the VMH will be altered by recurrent episodes of hypoglycemia. Further, we propose that leptin affects the sensitivity of glucose response neurons to interstitial glucose concentrations thereby altering the glycemic threshold for activation of glucoregulatory systems in the VMH.